Introduction

In humans, oxalate is an end product of metabolism. Absorbed from gut and produced endogenously, it must be excreted to prevent systemic oxalosis. Due to low solubility of Ca oxalate (CaOx), primary hyperoxaluria, caused by enzymatic deficiency, produces nephrolithiasis, nephrocalcinosis, and progressive renal failure. Less recognized is subacute insidious nephropathy from secondary causes like excessive vitamin C and malabsorption. Vitamin C is a precursor of oxalate, liable to produce hyperoxaluria [1–5]. It can also increase oxalate absorption, further accentuating the hyperoxaluria. In malabsorption, Ca chelates with fatty acids, generating enteric hyperoxaluria. Chronically, these risk factors predispose to nephrolithiasis and progressive renal failure, similar to primary hyperoxaluria [6, 7]. We here report a patient with severe renal failure due to these acquired risk factors, plus dehydration and hypocitraturia from diarrhea-induced metabolic acidosis. He responded well to stopping vitamin C and low oxalate diet, regaining enough function to avoid chronic dialysis.

Case Presentation

A 73-year-old man was hospitalized for chronic diarrhea and serum creatinine of 8.4 mg/dL (vs. 1.2, 1.8, and 3.1, respectively, 4 months, 5 weeks, and 8 days earlier) (Fig 1a). He had a past history of chronic alcoholism, atrial fibrillation, hypertension, heart failure, and hypothyroidism (all resolved or controlled).

Figure 1

Serum creatinine, urine oxalate:creatinine ratio, and creatinine clearance vs. clinical timeline. (a) The chart shows the trend of serum creatinine (gray bars, with the values shown on the left axis), starting from a baseline of 1.2 mg/dL just over 4 months ago, gradually increasing up to 3.1 mg/dL 8 days ago, and rapidly increasing to 8.4 mg/dL on admission (day 0). The urine oxalate:creatinine ratio (red squares connected by lines, with values shown on the right axis) clearly shows hyperoxaluria at admission (0.084 at day 1, compared to a normal of 0.035). Vitamin C was stopped on day 4, and creatinine started improving after 2 days. (b) Renal function in terms of creatinine clearance (% of normal) is also shown.

On examination, he appeared chronically ill, afebrile, alert, and fully oriented. Blood pressure was 121/75 mmHg. O2 saturation was normal. He weighed 68 Kg, 2 Kg lighter than 3 months ago. His lungs were clear and heart rhythm was sinus. His abdomen and extremities were normal, without edema or asterixis.

Since urinalysis was negative and proteinuria was minimal, oxalate-induced tubulointerstitial nephritis was proposed, given history of alcoholism, chronic diarrhea, and high-dose vitamin C. On day 2, 24-hour urine was submitted for oxalate. Given his weight loss, renal failure, and hypercalcemia, multiple myeloma was considered unlikely given negative serum and urine protein electrophoresis and negative bone marrow exam. Other causes for hypercalcemia were excluded by normal PTH, PTH-related peptide, 1,25 (OH)2 vit D, 25 OH vit D, alkaline phosphatase, and free T4. Neoplasms were excluded by CT scans of chest, abdomen, and pelvis, and endoscopies.

His creatinine continued to rise despite drinking plenty of fluids and stopping lasix and lisinopril (Fig 1a). Salt depletion was excluded by lack of fall in creatinine despite several liters of saline, arguing against dehydration as the cause for his acute renal failure. While still waiting for urine oxalate results, which were delayed due to erroneous submission of un-acidified aliquot, we stopped vitamin C on day 4. Hypercalcemia was attributed to CaCO3, vitamins A and D, as it resolved off these agents. Diarrhea was attributed to MgO, vitamin A, and niacin, all known to have cathartic potential. Indeed, diarrhea resolved once they were stopped. These responses reinforced the suspicion of nephrotoxic "over-the-counter" medications.

Slides from left kidney biopsy and CT image of abdomen. There is extensive interstitial fibrosis and tubular atrophy, with marked medial fibrosis in an artery on the lower right (trichrome/10x) (a); bright crystals are seen under partial polarization within the lumens of two tubules (arrows) (H&E/20x) (b). A 10 mm calculus is seen in the right extra renal pelvis (arrow) in the CT (c).

The hyperoxaluria was attributable to vitamin C, as it resolved on discontinuation of vitamin C (urine oxalate:creatinine ratio 0.052, Fig 1a). A low oxalate diet further reduced this ratio to 0.039 and to 0.028 (Fig 1a). We did not measure urine citrate during his peak renal failure since severe metabolic acidosis is expected to non-specifically suppress excretion. However, 11 and 30 days post-discharge, when serum HCO3 approached normal (22 and 21 mM) and creatinine substantially improved (4.6 and 2.9 mg/dL), we still documented markedly reduced urine citrate (respectively, 14 mg and 18 mg per gram of creatinine; normal being ≥ 250). These results suggest significant ongoing metabolic acidosis preceding or paralleling the steady rise in serum creatinine in previous months.

Discussion

Urinary oxalate is derived from endogenous production and absorption from exogenous sources. Hyperoxaluria (urine oxalate above the normal range of 10–35 mg/24 hr) can be primary or secondary. Primary hyperoxaluria results from genetic defects in glyoxylate metabolism, producing nephrolithiasis, nephrocalcinosis, and progressive renal insufficiency [9]. Secondary hyperoxaluria is acquired from enteric causes or ethyl glycol intoxication. Normally, Ca binds most of the intestinal oxalate, with subsequent stool CaOx elimination. Accordingly, only 4 to 12% of enteric oxalate is normally absorbed. After small bowel bypass, Ca complexes with poorly absorbed fatty acids, leaving behind excess unbound oxalate for absorption, 65 to 80% of which occurs in the colon [6, 7]. This mechanism also explains the enteric hyperoxaluria in chronic diarrhea and malabsorption.

Another important but under-appreciated etiology of secondary hyperoxaluria is increased synthesis from vitamin C [1–5]. We previously reported the quantitative dose-response relationship in a patient receiving vitamin C solely from parenteral nutrition [5]. If coexisting, malabsorption and high-dose vitamin C could potentiate the hyperoxaluria induced by each other.

Clinically, hyperoxaluria presents in one of several ways, depending on the severity, chronicity, etiologies and co-factors. First, at one extreme, as in ethylene glycol intoxication, fulminant acute renal failure from intraluminal obstruction can develop, due to excessive oxalate production and profound hyperoxaluria. Second, at the other end, intermittent hyperoxaluria could cause episodic painful renal colic from small punctuate Ca Ox calculi. Despite short-term morbidities, few suffer from serious long-term renal insufficiency. The third mode of clinical presentation is illustrated by primary hyperoxaluria.

Our patient demonstrates the fourth mode of manifestation in that insidious renal failure, easily missed, slowly evolves over weeks to months, unbeknown to patients and physicians until renal function is compromised by >50–70 %. Typically, for diffuse intraluminal crystal deposits and extensive interstitial fibrosis to develop, the course is protracted. While the first three modes (ethylene glycol intoxication, episodic stone attacks, and primary hyperoxaluria) are clinically symptomatic and promptly treated, the 4th mode is generally quiescent, asymptomatic, undiagnosed, and untreated for months, like our patient, unless tests reveal incidental unexpected progressive renal failure.

Unfortunately, vitamin C-induced hyperoxaluria is often missed or diagnosed late in the course of renal failure, and for several reasons. One, increasingly individuals take daily multi-vitamins or high-dose vitamin C on their own. Second, current commercial preparations contain vitamin C typically several-fold over the adult daily requirement of 60 mg. Most juices, soft drinks, and diet supplements contain > 120 mg of vitamin C per 8 oz. These add greatly to food-derived oxalate. Third, self-prescribed medications are not routinely checked or discovered by physicians, as the potential adverse hyperoxaluric consequence is generally unrecognized. Fourth, the causal relationship between hyperoxaluria and renal failure is also under-appreciated. Finally, when advanced renal insufficiency emerges, the focus is shifted to uremia management. Identifying and defining the etiology is seldom exhaustively undertaken or usually unsuccessful.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

SR did the initial workup and follow-up. KL made the diagnosis and treated the patient. Both SR and KL plotted the graphs and drafted the manuscript. WK was responsible for interpretation of biopsy findings. All authors read and approved the final manuscript.

Authors’ Affiliations

(1)

Department of Medicine, The University of Oklahoma Health Sciences Center

(2)

Department of Pathology, The University of Oklahoma Health Sciences Center

(3)

Department of Medicine, The University of Oklahoma Health Sciences Center

Copyright

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.